Progress Towards Modeling the Ablation Response of NuSil-Coated PICA

The Mars Science Laboratory (MSL) Entry, Descent and Landing Instrumentation (MEDLI) collected in-flight data largely used by the ablation community to verify and validate physics-based models for the response of the Phenolic Impregnated Carbon Ablator (PICA) material [1-4]. MEDLI data were recently used to guide the development of NASAs high-fidelity material response models for PICA, implemented in the Porous material Analysis Toolbox based on OpenFOAM (PATO) software [5-6]. A follow-up instrumentation suite, MEDLI2, is planned for the upcoming Mars 2020 mission [7] after the large scientific impact of MEDLI. Recent analyses performed as part of MEDLI2 development draw the attention to significant effects of a protective coating to the aerothermal response of PICA. NuSil, a silicone-based overcoat sprayed onto the MSL heatshield as contamination control, is currently neglected in PICA ablation models. To mitigate the spread of phenolic dust from PICA, NuSil was applied to the entire MSL heatshield, including the MEDLI plugs. NuSil is a space grade designation of the siloxane copolymer, primarily used to protect against atomic oxygen erosion in the Low Earth Orbit environment. Ground testing of PICA-NuSil (PICA-N) models all exhibited surface temperature jumps of the order of 200 K due to oxide scale formation and subsequent NuSil burn-off. It is therefore critical to include a model for the aerothermal response of the coating in ongoing code development and validation efforts

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD

Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

Biomarcadors; Ibrutinib; Limfoma no hodgkinBiomarkers; Ibrutinib; Non-hodgkin's lymphomaBiomarcadores; Ibrutinib; Linfoma no hodgkinWe analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88 , or TNFRSF14 , while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell–like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.Sponsored by Janssen Research & Development, LLC

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Background: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. Methods and Results: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). Conclusion: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia

Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves

Brentuximab vedotin as a bridge to combination chemotherapy in gray zone lymphoma with severe liver impairment: a case report

BackgroundGray zone lymphoma (GZL) is a rare lymphoma subtype characterized by features intermediate between diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL). The optimal first-line treatment for GZL remains undefined, particularly for patients with poor performance status or baseline organ impairment. Brentuximab vedotin (BV), a targeted therapy that binds to CD30, a TNFR superfamily member involved in NF-kB signaling, has shown promise in the treatment of CD30-positive lymphomas. However, its use in GZL, especially in patients with severe liver impairment, has not been reported previously.Case descriptionWe present a case of a 37-year-old male with GZL and severe liver impairment at initial presentation. The patient initially received monotherapy with BV, which resulted in a marked improvement in liver enzymes and bilirubin levels. Subsequently, combination cytotoxic chemotherapy consisting of dose-adjusted etoposide, prednisone, cyclophosphamide, and doxorubicin (DA-EP_CH) was added. Repeat imaging revealed near complete resolution of lymphadenopathy and significant reduction in hepatosplenomegaly. The patient completed a full course of chemotherapy and achieved a complete response. Follow-up examinations showed no evidence of recurrent disease, and the patient resumed full-time work.DiscussionGZL poses diagnostic challenges due to its overlapping features with DLBCL and cHL. Accurate diagnosis relies on comprehensive histopathological evaluation, immunophenotyping, and molecular analysis. The optimal first-line treatment for GZL remains uncertain. BV shows promise as an addition to chemotherapy in GZL, even in the presence of severe liver impairment. The molecular pathogenesis of GZL is complex and heterogeneous, frequently involving aberrant NF-kB signaling and impaired apoptosis regulation via loss of TP53 expression. Understanding the underlying molecular mechanisms is essential for developing targeted therapies and identifying predictive biomarkers for treatment response.ConclusionThis case demonstrates the successful use of BV as a bridge to cytotoxic chemotherapy in a GZL patient with severe liver impairment, highlighting its potential safety and efficacy even in the setting of end-organ failure. Further investigation is warranted to define optimal treatment strategies, identify predictive biomarkers, and improve outcomes for patients with this rare and challenging lymphoma subtype

Progress Towards Modeling the Mars Science Laboratory PICA-NuSil Heatshield

The data collected by the Mars Science Laboratory (MSL) Entry, Descent and Landing Instrumentation, MEDLI, have become an established reference to assess the performance of engineering models of the Phenolic Impregnated Carbon Ablator (PICA) and to validate hypersonic computational fluid dynamics (CFD) tools for entry systems. MEDLI measurements are also extensively used as validation reference for current developments of high-fidelity material response models for PICA. So large has been the scientific output and impact of MEDLI that a follow-up instrumentation suite MEDLI2 is underway for the upcoming Mars 2020 mission.A feature neglected thus far in the modeling of the MSL heatshield, is the presence of a silicone-based room temperature vulcanizing coating designated NuSil CV-1144-0. NuSil was used to coat the entire MSL heatshield, including the MEDLI plugs, to mitigate the spread of phenolic dust from PICA, and limit contamination during clean room operations. NuSil CV-1144-0 is a space grade siloxane copolymer, designed as an oxygen protection barrier for extreme low temperature environment.Assessments conducted during MSL development demonstrated that the presence of NuSil had no adverse effect on the performance of PICA. However, evidence from ground testing of PICA-NuSil (PICA-N) models in the HyMETS arc-jet test facility suggests that the silicone changes the high temperature response of PICA. It is therefore critical to assess the importance of modeling the coating in ongoing code validation efforts

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies